Indole Alkaloids as Biased Opioid Receptor Modulators

Summary

Indole alkaloids such as ibogaine and mitragynine activate μ-opioid receptors as biased full or partial agonists that recruit β-arrestin much less than non-biased agonists. Because β-arrestin recruitment is linked to adverse effects like respiratory depression, this biased activation may limit those effects. The molecular mechanism likely involves the indole structure altering the spatial orientation of amino acid residues in transmembrane regions 2 and 3 and extracellular helix 8. These naturally occurring compounds may provide a scaffold for developing new opioid modulators with an improved risk-to-benefit ratio.

Study at a glance

Abstract

Background: Opioid receptors are a commonly used target for treatment of pain conditions. Most opioids used in therapy are linked to adverse effects such as tolerance, dependence, and respiratory depression. Indole alkaloids acting on opioid receptors may provide a novel molecular mechanism to confer analgesic effects. Results: Indole alkaloids such as ibogaine and mitragynine act on μ-opioid receptors as biased full or partial agonists that do not, or much less strongly, recruit β-arrestin compared to non-biased agonists. The recruitment of β-arrestin has been linked to adverse effects, most notably substantial respiratory depression. The molecular mechanism of biased activation has been proposed to be associated with accommodation of the indole structure that leads to a different spatial orientation of amino acid residues in transmembrane regions 2 and 3 of the μ-opioid receptor as well as extracellular helix 8. Conclusions: Naturally occurring indole alkaloids show biased G-protein coupled activation of opioid receptors with limited recruitment of β-arrestin, thus limiting commonly observed adverse effects. Indole alkaloids may present a feasible structure to develop new biased opioid modulators with an improved risk-to-benefit ratio.